This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. CD73 is a glycosylphosphatidylinositol (GPI)-linked membrane protein that catalyzes the extracellular dephosphorylation of AMP to adenosine. Thrombomodulin (TM) is a type I transmembrane protein located on the surface of endothelial cells. It serves as a thrombin modulator, since thrombin's substrate specificity is switched once binding to TM. In this study, we proposed that CD73-generated adenosine regulates TM expression and TM is a target of the CD73-generated adenosine signaling pathway. The specific aims are: 1. To delineate the pathway of CD73 regulated TM expression and the impact on TM functions in cultured endothelial cells. 2. To study the role of CD73 on TM regulation and the impact on TM functions in mouse model. 3. To study the role of anti-coagulation system involved in CD73 functions. Our preliminary results indicated that TM expression levels were up-regulated by an adenosine receptor agonist in vitro and in vivo. CD73-generated adenosine also can increase TM expression in vitro. In this proposal, we will identify the adenosine receptor subtype responsible for TM regulation and the downstream effectors. The impact on TM functions will be characterized by protein C activation on endothelial cells. We have compared TM expression levels in CD73-/- mice to that in wild type mice under normal conditions. These comparisons will be carried out under inflammatory conditions. The impact on TM functions will be characterized by measuring APC level in plasma in wild type mice and CD73-/- mice under inflammatory conditions. The impact of anti-coagulation system on CD73 functions will also be studied under several experimental settings.